scholarly journals Alkylphosphocholines inhibit choline uptake and phosphatidylcholine biosynthesis in rat sympathetic neurons and impair axonal extension

1995 ◽  
Vol 312 (2) ◽  
pp. 411-417 ◽  
Author(s):  
E Posse de Chaves ◽  
D E Vance ◽  
R B Campenot ◽  
J E Vance
Keyword(s):  
Sympathetic Neurons ◽  
Axon Growth ◽  
Inhibitory Effect ◽  
Membrane Lipid ◽  
Choline Uptake ◽  
Axonal Membrane ◽  
Local Synthesis ◽  
Axonal Elongation ◽  
Phosphocholine Cytidylyltransferase ◽  
Phosphatidylcholine Synthesis

At least 50% of the major axonal membrane lipid, phosphatidylcholine, of rat sympathetic neurons is synthesized in situ in axons [Posse de Chaves, Vance, Campenot and Vance (1995) J. Cell Biol. 128, 913-918]. In the same study we reported that, in a choline-deficient model for neuron growth, phosphatidylcholine synthesis in cell bodies is neither necessary nor sufficient for growth of distal axons. Rather, the local synthesis of phosphatidylcholine in distal axons is required for normal axon growth. We have now used three alkylphosphocholines (hexadecylphosphocholine, dodecylphosphocholine and octadecylphosphocholine) as inhibitors of PtdCho biosynthesis in a compartmented model for culture of rat sympathetic neurons. The experiments reveal that alkylphosphocholines decrease the uptake of choline into these neurons and inhibit PtdCho synthesis, but not via an effect on the activity of the enzyme CTP: phosphocholine cytidylyltransferase. We also show that when the distal axons, but not the cell bodies, are exposed to alkylphosphocholines, axonal elongation is inhibited, which is consistent with the hypothesis that phosphatidylcholine synthesis in axons, but not in cell bodies, is required for axonal elongation. The inhibitory effect of alkylphosphocholines on axon growth is most likely not mediated via a decrease in the activity of protein kinase C, since when this enzyme activity is down-regulated by treatment of the cells with phorbol ester, the alkylphosphocholines retain their ability to inhibit axonal growth.

scholarly journals Axonal synthesis of phosphatidylcholine is required for normal axonal growth in rat sympathetic neurons.

1995 ◽  
Vol 128 (5) ◽  
pp. 913-918 ◽  
Author(s):  
E Posse de Chaves ◽  
D E Vance ◽  
R B Campenot ◽  
J E Vance
Keyword(s):  
Sympathetic Neurons ◽  
Specific Radioactivity ◽  
Normal Growth ◽  
Neurite Growth ◽  
Relative Importance ◽  
Double Labeling ◽  
Local Synthesis ◽  
Deficient Medium ◽  
Phosphatidylcholine Synthesis ◽  
Cells Cultured

The goal of this study was to assess the relative importance of the axonal synthesis of phosphatidylcholine for neurite growth using rat sympathetic neurons maintained in compartmented culture dishes. In a double-labeling experiment [14C]choline was added to compartments that contained only distal axons and [3H]choline was added to compartments that contained cell bodies and proximal axons. The specific radioactivity of labeled choline was equalized in all compartments. The results show that approximately 50% of phosphatidylcholine in distal axons is locally synthesized by axons. The requirement of axonal phosphatidylcholine synthesis for neurite growth was investigated. The neurons were supplied with medium lacking choline, an essential substrate for phosphatidylcholine synthesis. In the cells grown in choline-deficient medium for 5 d, the incorporation of [3H]palmitate into phosphatidylcholine was reduced by 54% compared to that in cells cultured in choline-containing medium. When phosphatidylcholine synthesis was reduced in this manner in distal axons alone, growth of distal neurites was inhibited by approximately 50%. In contrast, when phosphatidylcholine synthesis was inhibited only in the compartment containing cell bodies with proximal axons, growth of distal neurites continued normally. These experiments imply that the synthesis of phosphatidylcholine in cell bodies is neither necessary nor sufficient for growth of distal neurites. Rather, the local synthesis of phosphatidylcholine in distal axons is required for normal growth.

scholarly journals Fatty acids reverse the cyclic AMP inhibition of triacylglycerol and phosphatidylcholine synthesis in rat hepatocytes

1983 ◽  
Vol 216 (1) ◽  
pp. 129-136 ◽  
Author(s):  
S L Pelech ◽  
P H Pritchard ◽  
D N Brindley ◽  
D E Vance
Keyword(s):  
Fatty Acids ◽  
Cyclic Amp ◽  
Rat Hepatocytes ◽  
Phosphocholine Cytidylyltransferase ◽  
Triacylglycerol Synthesis ◽  
Monolayer Cultures ◽  
Membrane Bound ◽  
Amp Inhibition ◽  
Phosphatidylcholine Synthesis

The influence of cyclic AMP analogues and fatty acids on glycerolipid biosynthesis in monolayer cultures of rat hepatocytes was investigated. Chlorophenylthio-cyclic AMP and adenosine 3′:5′-cyclic phosphorothioate inhibited the rate of triacylglycerol synthesis from [1(3)-3H]glycerol, and phosphatidylcholine synthesis from [Me-3H]-choline. Supplementation of the hepatocytes with palmitate (1 mM) reversed chlorophenylthio-cyclic AMP inhibition of triacylglycerol synthesis. Similarly, cyclic AMP analogue-inhibition of phosphatidylcholine synthesis was abolished when the cells were simultaneously incubated with oleate (3 mM). Reactivation of phosphatidylcholine synthesis in chlorophenylthio-cyclic AMP-supplemented cells with oleate was accompanied by conversion of CTP: phosphocholine cytidylyltransferase into the membrane-bound form, since these cells released the enzyme more slowly after treatment with digitonin. The opposing actions of cyclic AMP and fatty acids are discussed in relation to the regulation of glycerolipid biosynthesis during starvation, diabetes and stress.

scholarly journals Axons provide the secretory machinery for trafficking of voltage-gated sodium channels in peripheral nerve

2016 ◽  
Vol 113 (7) ◽  
pp. 1823-1828 ◽  
Author(s):  
Carolina González ◽  
José Cánovas ◽  
Javiera Fresno ◽  
Eduardo Couve ◽  
Felipe A. Court ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Neural Function ◽  
Axonal Membrane ◽  
Local Synthesis ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

The regulation of the axonal proteome is key to generate and maintain neural function. Fast and slow axoplasmic waves have been known for decades, but alternative mechanisms to control the abundance of axonal proteins based on local synthesis have also been identified. The presence of the endoplasmic reticulum has been documented in peripheral axons, but it is still unknown whether this localized organelle participates in the delivery of axonal membrane proteins. Voltage-gated sodium channels are responsible for action potentials and are mostly concentrated in the axon initial segment and nodes of Ranvier. Despite their fundamental role, little is known about the intracellular trafficking mechanisms that govern their availability in mature axons. Here we describe the secretory machinery in axons and its contribution to plasma membrane delivery of sodium channels. The distribution of axonal secretory components was evaluated in axons of the sciatic nerve and in spinal nerve axons after in vivo electroporation. Intracellular protein trafficking was pharmacologically blocked in vivo and in vitro. Axonal voltage-gated sodium channel mRNA and local trafficking were examined by RT-PCR and a retention-release methodology. We demonstrate that mature axons contain components of the endoplasmic reticulum and other biosynthetic organelles. Axonal organelles and sodium channel localization are sensitive to local blockade of the endoplasmic reticulum to Golgi transport. More importantly, secretory organelles are capable of delivering sodium channels to the plasma membrane in isolated axons, demonstrating an intrinsic capacity of the axonal biosynthetic route in regulating the axonal proteome in mammalian axons.

scholarly journals Alterations in the Anandamide Metabolism in the Development of Neuropathic Pain

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Natalia Malek ◽  
Mateusz Kucharczyk ◽  
Katarzyna Starowicz
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Mrna Level ◽  
Inhibitory Effect ◽  
Lumbar Spinal Cord ◽  
Local Synthesis ◽  
Time Points ◽  
Pain Pathways ◽  
Lumbar Spinal ◽  
Synthesis And Degradation

Endocannabinoids (EC), particularly anandamide (AEA), released constitutively in pain pathways might be accountable for the inhibitory effect on nociceptors. Pathogenesis of neuropathic pain may reflect complex remodeling of the dorsal root ganglia (DRGs) and spinal cord EC system. Multiple pathways involved both in the biosynthesis and degradation of AEA have been suggested. We investigated the local synthesis and degradation features of AEA in DRGs and spinal cord during the development and maintenance of pain in a model of chronic constriction injury (CCI). All AEA synthesis and degradation enzymes are present on the mRNA level in DRGs and lumbar spinal cord of intact as well as CCI-treated animals. Deregulation of EC system components was consistent with development of pain phenotype at days 3, 7, and 14 after CCI. The expression levels of enzymes involved in AEA degradation was significantly upregulated ipsilateral in DRGs and spinal cord at different time points. Expression of enzymes of the alternative, sPLA2-dependent and PLC-dependent, AEA synthesis pathways was elevated in both of the analyzed structures at all time points. Our data have shown an alteration of alternative AEA synthesis and degradation pathways, which might contribute to the variation of AEA levels and neuropathic pain development.

Membrane Lipid Biosynthesis As a Potential Therapeutic Target in Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1836-1836
Author(s):  
Carolyne Bardeleben ◽  
Alan Lichtenstein
Keyword(s):  
Multiple Myeloma ◽  
Er Stress ◽  
Cell Lines ◽  
Cell Apoptosis ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Membrane Lipid ◽  
Dependent Manner ◽  
Kennedy Pathway ◽  
Phosphatidylcholine Synthesis

Abstract Abstract 1836 Phosphatidylcholine (PC) is the most prominent phospholipid in mammalian endoplasmic reticulum (ER) membranes. The rate-limiting step in PC synthesis through the Kennedy pathway is the conversion of phosphocholine + cytidine triphosphate (CTP) to cytidine diphosphocholine, (CDP)-choline, via the enzyme CTP:phosphocholine cytidylyltransferase (CCT) (see figure). Multiple myeloma (MM) cells may be particularly dependent on this biosynthetic reaction because of their high consistent level of ER stress and requirement to continuously replenish ER membranes. Indeed, CCT-null mice have a defect in differentiation of B lymphocytes to plasma cells and deficiencies in Ig synthesis. To test whether this pathway remains critical in survival of malignant MM cells, we exposed MM cell lines to an inhibitor shown to inhibit CCT activity, HexPC. HexPC induced apoptosis in all MM cell lines in a concentration- and time-dependent manner. The addition of lysophosphatidylcholine (LPC), presumably converted to PC independently of the Kennedy pathway, completely rescued MM cell apoptosis. In contrast, similar concentrations of LPC in the same cell lines could not rescue apoptosis induced by bortezomib. An additional intervention to inhibit phosphatidylcholine synthesis, namely inducing pyrimidine starvation, also resulted in MM cell apoptosis and down-regulation of CDP-choline levels. Apoptosis of MM cells induced by HexPC was associated with induction of ER stress as shown by enhanced phosphorylation of IRE1 and eIF-2alpha. This ER stress was also prevented when LPC was added to HexPC although LPC could not prevent similar ER stress induced by bortezomib. These results underscore the importance of this phosphatidylcholine synthesis pathway in MM cells and provide new targets for future therapy. Disclosures: No relevant conflicts of interest to declare.

Vascular-derived artemin: a determinant of vascular sympathetic innervation?

2007 ◽  
Vol 293 (1) ◽  
pp. H266-H273 ◽  
Author(s):  
Deborah H. Damon ◽  
Jaclyn A. teRiele ◽  
Stephen B. Marko
Keyword(s):  
Important Determinant ◽  
Sympathetic Neurons ◽  
Sympathetic Innervation ◽  
Axon Growth ◽  
Neurite Growth ◽  
Sympathetic Ganglia ◽  
Neonatal Rat ◽  
Rt Pcr ◽  
Adult Rats ◽  
Sympathetic Axon

Vascular sympathetic innervation is an important determinant of blood pressure and blood flow. The mechanisms that determine vascular sympathetic innervation are not well understood. The present study tests the hypothesis that vascular-derived artemin promotes the development of sympathetic innervation to blood vessels by promoting sympathetic axon growth. RT-PCR and Western analyses indicate that artemin is expressed by cultured vascular smooth muscle and arteries, and artemin coreceptors, glial cell-derived neurotrophic factor family receptor α3 and ret, are expressed by postganglionic sympathetic neurons. The effects of artemin on axon growth were assessed on explants of neonatal rat sympathetic ganglia. In the presence, but not in the absence, of nerve growth factor, exogenous artemin stimulated neurite growth. Femoral arteries (FA) from adult rats contain artemin, and these arteries stimulated sympathetic neurite growth. Growth in the presence of FA was 92.2 ± 11.9 mm, and that in the absence of FA was 26.3 ± 5.4 mm ( P < 0.05). FA stimulation of axon growth was reduced by an antibody that neutralized the activity of artemin ( P < 0.05). These data indicate that artemin is expressed in arteries, and its receptors are expressed and functional in the postganglionic sympathetic neurons that innervate them. This suggests that artemin may be a determinant of vascular sympathetic innervation.

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